Bismuth-containing pharmaceutical compositions, particularly pharmaceutical suspensions, are well known for use in treating a variety of gastrointestinal disorders including nausea, heartburn and diarrhea. Illustrative bismuth-containing suspensions currently and/or previously on the market include Pepto-Bismol® of Proctor & Gamble Company, several similar retail branded bismuth-containing suspensions (illustratively including those sold by Walgreen's®, Rite-Aid®, Spartan®, and Meijer®), and Pabizol with Paregoric of Rexall. Bismuth-containing compositions are described generally in Handbook of Nonprescription Drugs, 8th Edition, American Pharmaceutical Association, Washington D.C.; 1986, pages 73–74. In addition to a bismuth-containing compound, many of these products further contain, inter alia, one or more anti-microbial preservatives, magnesium aluminum silicate and other suspending agents, colorant(s), etc.
U.S. Pat. No. 4,940,695 to Coveney discloses pharmaceutical compositions suitable for oral administration comprising pharmaceutically-acceptable bismuth-containing agents, pharmaceutically-acceptable non-ionic cellulose ether polymers, and magnesium aluminum silicate.
U.S. Pat. No. 5,013,560 to Stentz discloses microbially stable liquid pharmaceutical suspensions for oral administration comprising a bismuth-containing pharmaceutical agent, benzoic acid, sorbic acid, a suspension system preferably comprising magnesium aluminum silicate, and water, wherein the suspensions have a pH within the range of about 3.0 to about 5.5.
European Patent Application No. 0 217 440 to Gonsalves discloses pharmaceutical compositions for treatment of gastrointestinal disorders comprising 1.5% to 5% of a pharmaceutically-acceptable bismuth salt, 0.3% to 1.3% magnesium aluminum silicate, 0.5% to 0.85% xanthan gum, and water, having a defined ratio of magnesium aluminum silicate to xanthan gum.
Many currently marketed bismuth-containing suspensions exhibit the undesirable characteristic of upward pH drift which is accompanied by several potential adverse consequences. For example, most pharmaceutically acceptable anti-microbial preservatives become less effective at higher pH levels. Therefore, suspensions which exhibit an increase in pH during storage more quickly reach pH levels at which one or more anti-microbial preservatives present in the suspension tend to be less effective or completely ineffective. Consequently, such suspensions more rapidly become susceptible to microbial contamination and have a relatively short shelf life. Additionally, many common pharmaceutical excipients, for example colorants such as indigo carmine and turmeric, are pH sensitive. Suspensions which exhibit pH drift and comprise pH-sensitive excipients tend to change appearance and/or color over time. Such changes are particularly undesirable from a commercial acceptance and product recognition standpoint.
It is well known that suspensions having a low pH tend to taste bitter. Since, as indicated above, many anti-microbial preservatives do not function well at higher pH's (e.g. greater than about 5), suspensions which tend to drift upward in pH must therefore be prepared at a relatively low pH in order to maintain anti-microbial effectiveness while still possessing a suitable shelf life. Consequently, such low-pH suspensions have a bitter taste and/or must utilize elaborate taste-masking systems.
Even where preservatives which are effective at high pH levels are employed, suspensions having a pH greater than about 8 are generally considered to be unpalatable. Therefore, the shelf life of a suspension which exhibits upward drift may also be limited by unpleasant taste properties at higher pH levels.
If a bismuth-containing pharmaceutical composition could be prepared which exhibits reduced upward pH drift, a significant advance in the use of bismuth-containing compositions in treating gastrointestinal disorders would result.